This invention relates to the process for the preparation of 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, also designated etodolac, disclosed as a potent antiinflammatory and analgesic compound in Demerson et al., U.S. Pat. No. 3,939,178.
Preparations for pyrano[3,4-b]indoles have been previously described in Demerson et al., U.S. Pat. Nos. 3,939,178 and 4,012,417 and in Demerson et al., J. Med. Chem., 19, 391 (1976).
Demerson et al., U.S. Pat. Nos. 3,939,178 and 4,012,417 disclose reaction of substituted tryptophols with keto ester to produce pyrano[3,4-b]indoles (see col. 9, lines 5 to 35). Etodolac is produced according to Example 477 of U.S. Pat. No. 4,012,417 by the reaction of 7-ethyltryptophol and the keto ester, ethyl propionylacetate, followed by alkaline hydrolysis. The 7-ethyltryptophol is produced by the reaction of 2-ethylphenylhydrazine with 4-hydroxybutyraldehyde.
Demerson et al., J. Med. Chem., 19, 391 (1976) also discloses the preparation of pyrano[3,4-b]indoles by the reaction of substituted tryptophols with keto esters. The 7-ethyltryptophol, necessary for the production of etodolac, is prepared by the reduction of ethyl 7-ethyl-3-indolylglyoxylate with LiAlH.sub.4 (page 394, right column). The glyoxylate is produced by the reaction of 7-ethylindole with oxalyl chloride. The 7-ethylindole is produced from 2-ethylaniline in a thee step process. Demerson et al., also discloses the preparation of 7-cyclopropyltryptophol by the reaction of 2-cyclopropylphenylhydrazine hydrochloride with 2,3-dihydrofuran using the method described by I. I. Grandberg and T. P. Moskvina, Khim. Geterotsikl, Soedin., 1366 (1972).